title: Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.
abstract: Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.
authors.affiliation: Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Yoshimoto
authors.forename: Tze Mun
authors.initials: TM
authors.lastname: Loo
authors.forename: Koji
authors.initials: K
authors.lastname: Atarashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanda
authors.forename: Seidai
authors.initials: S
authors.lastname: Sato
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Kenshiro
authors.initials: K
authors.lastname: Oshima
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Morita
authors.forename: Masahira
authors.initials: M
authors.lastname: Hattori
authors.forename: Masahisa
authors.initials: M
authors.lastname: Hattori
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
authors.forename: Naoko
authors.initials: N
authors.lastname: Ohtani
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003840:Deoxycholic Acid / Q000097:blood / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000473:pathology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000172:deficiency; D008113:Liver Neoplasms / Q000150:complications / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism*; D010641:Phenotype; D012307:Risk Factors
chemical_list: D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D016207:Cytokines; D004041:Dietary Fats; D053583:Interleukin-1beta; D003840:Deoxycholic Acid